Cross-species models of human melanoma

Abstract

Although transformation of melanocytes to melanoma is rare, the rapid growth, systemic spread, as well as the chemoresistance of melanoma present significant challenges for patient care. Here we review animal models of melanoma, including murine, canine, equine, and zebrafish models, and detail the immense contribution these models have made to our knowledge of human melanoma development, and to melanocyte biology. We also highlight the opportunities for cross-species comparative genomic studies of melanoma to identify the key molecular events that drive this complex disease.

Keywords: cross-species analysis; genome analysis; melanoma.

Figure 1

Established melanoma pathways. The two major signalling pathways implicated in melanoma are the mitogen‐activated protein kinase and the phosphatidylinositol‐4,5‐bisphosphate 3‐kinase pathways, which are in red and green, respectively. Key genes include c‐KIT (pink), CDK (blue), GNAQ/GNA11 (brown), MITF (orange), NRAS (yellow), and P53/BCL (purple). MC1R, which is involved in skin pigmentation, and TERT and POT1, which are involved in telomere regulation, are also shown. This figure was modified from Vidwans et al 142 under the Creative Commons Attribution License. The lines shown indicate known interactions between pathways or molecules.

Figure 2

Naevi and melanomas driven by oncogenic forms of Braf and NRAS. (A, B) Naevi developing in adult Braf^V618E mice 48. Naevi generally became visible 6–8 weeks after the induction of Braf^V618E expression. (C, D) Melanoma from the same Braf^V618E model. D shows an invasive malignant melanoma with evidence of infiltration and destruction of the overlying surface epithelium and invasion into the subcutaneous adipose tissue. The average latency to melanoma formation was 426 days in this model. (E) H&E‐stained section of an ocular melanoma, with melanoma cell infiltration of the lens and the subretinal tissues, that developed in a 13‐week‐old Tyr::NRAS^Q61K mouse 135. Original magnification × 50.

Figure 3

Canine, equine, and zebrafish melanoma. (A) A canine melanoma developing in the nasal cavity and (B) spreading to the viscera, particularly the liver. (C) An equine melanoma showing multinodular dermal lesions around the tail base and masses expanding into the pelvic canal and regional nodes. (D) An equine spleen with multiple malignant melanomas, and liver and lymph node from the same case. (E) Melanomas arising in a BRAF^V600E; mitf zebrafish and (F) in a BRAF^V600E; p53 zebrafish. The photographs in A and B were kindly provided by Jeff Caswell, Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada N1G2W1.